An Unusual Intramolecular Acetal Alkylation

Xiuchun Gao; Punit P. Seth; John K. Bitok; Nancy I. Totah

doi:10.1055/s-2005-863748

LETTER

An Unusual Intramolecular Acetal Alkylation

Xiuchun Gao, Punit P. Seth, John K. Bitok, Nancy I. Totah*
Department of Chemistry, Syracuse University, Syracuse, NY 13244, USA
Fax: +1(315)4434070; e-Mail: ntotah@syr.edu;

Abstract

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Abstract

Upon treatment with Grignard reagents, suitably functionalized cis-fused bicyclic ketone acetals undergo intramolecular acetal alkylation to provide oxabicyclo[3.3.1]nonane derivatives. This transformation results in the formation of up to three stereogenic centers with high levels of stereoselectivity. Product distribution and stereochemistry vary with substrate substitution and the Grignard reagent utilized.

Key words

acetals - alkylation - annulation - Grignard reagents - stereoselectivity

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References

Taken in part from the MS thesis of X. Gao, University of Iowa, 2001.

For reviews in this area, see:

<A NAME="RS11004ST-2A">2a</A> Mukaiyama T. Murakami M. Synthesis 1987, 1043

<A NAME="RS11004ST-2B">2b</A> Alexakis A. Mangeney P. Tetrahedron: Asymmetry 1990, 1: 477

<A NAME="RS11004ST-3A">3a</A> Schmitz E. Eichorn I. The Chemistry of the Ether Linkage Patai S. John Wiley and Sons; New York: 1967. p.309

<A NAME="RS11004ST-3B">3b</A> Greene TW. Wuts PGM. Protective Groups in Organic Synthesis 2nd ed.: John Wiley and Sons; New York: 1991.

<A NAME="RS11004ST-4A">4a</A> Quelet R. d’Angelo J. Bull. Soc. Chim. Fr. 1967, 3390

<A NAME="RS11004ST-4B">4b</A> Mukaiyama T. Ishikawa H. Chem Lett. 1975, 1051

<A NAME="RS11004ST-4C">4c</A> Trofimov BA. Korostova SE. Russ. Chem. Rev. 1987, 44: 41

<A NAME="RS11004ST-4D">4d</A> Lu T.-J. Cheng S.-M. Sheu L.-J. J. Org. Chem. 1998, 63: 2738

<A NAME="RS11004ST-5A">5a</A> Hudrlik PF. Peterson D. J. Am. Chem. Soc. 1975, 97: 1464

<A NAME="RS11004ST-5B">5b</A> Trost BM. Fleming I. Comprehensive Organic Synthesis Vol. 1: Pergamon Press; Oxford: 1991. p.789 ; and references therein

TMSCH₂Cl has previously been utilized in acetal cleavage processes. See:

<A NAME="RS11004ST-6A">6a</A> Chiang C.-C. Chen Y.-H. Hseih Y.-T. Luh T.-Y. J. Org. Chem. 2000, 65: 4694

<A NAME="RS11004ST-6B">6b</A> Hseih Y.-T. Luh T.-Y. Heterocycles 2000, 52: 1125

This structure was confirmed by X-ray crystallography. Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre (CCDC-254147). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

<A NAME="RS11004ST-8">8</A> For a related process, see: Huang J.-W. Chen C.-D. Leung M. Tetrahedron Lett. 1999, 40: 8647

The chelation-controlled cleavage of acetals with Grignard reagents has been reported. See, for example:

<A NAME="RS11004ST-9A">9a</A> Corcoran RC. Tetrahedron Lett. 1990, 31: 2101

<A NAME="RS11004ST-9B">9b</A> Cheng W.-L. Shaw Y.-J. Yeh S.-M. Kanakamma PP. Chen Y.-H. Chen C. Shieu J.-C. Lee G.-H. Wang Y. Luh T.-Y. J. Org. Chem. 1999, 64: 532

The regiochemistry of intermolecular addition (e.g. 9) was determined by evaluation of chemical shifts in the corresponding acetate.

<A NAME="RS11004ST-11A">11a</A> Blomberg C. Vreugdenhil AD. Homsma TJ. Recl. Trav. Chim. Pays-Bas 1963, 82: 355

<A NAME="RS11004ST-11B">11b</A> Westera G. Blomberg C. Bickelhaupt F. J. Organomet. Chem. 1978, 144: 285

<A NAME="RS11004ST-11C">11c</A> Mori I. Ishihara K. Flippin LA. Nazaki K. Yamamoto H. Bartlett PA. Heathcock CH. J. Org. Chem. 1990, 55: 6107

<A NAME="RS11004ST-11D">11d</A> Denmark SE. Almstead NG. J. Am. Chem. Soc. 1991, 113: 8089

<A NAME="RS11004ST-11E">11e</A> Sammakia T. Smith RS. J. Org. Chem. 1992, 57: 2997

Stereochemical assignments are supported by NOE studies.

General Methods.
All air sensitive reactions were performed in base washed, flame dried glassware under an atmosphere of argon. THF was dried over Na/benzophenone ketyl and was distilled just prior to use. Pyridine was distilled from CaH₂. Analytical thin layer chromatography was performed on EM silica gel 60F glass plates (0.25 mm). Flash column chromatography was performed using EM silica gel 60 (230-400 mesh). ¹H NMR spectra were recorded on Bruker AC-300 or WM-360 spectrometers. Chemical shifts are reported in ppm, downfield from tetramethylsilane using residual CHCl₃ as the internal standard (δ = 7.27 ppm). ¹³C NMR spectra were recorded on a Bruker WM-360 (90 MHz) spectrometer with complete proton decoupling. Chemical shifts are reported in ppm, downfield from tetramethylsilane using residual CHCl₃ as the internal standard (δ = 77.0 ppm). IR spectra were obtained with a Mattson Cygnus 25 instrument. Elemental Analyses were performed by Atlantic Microlab, Inc.; Norcross, GA.
General Procedure for Intramolecular Alkylation.
To a solution of ketone 1 (0.1 mmol) in 2 mL THF was added the Grignard reagent (3.4 mL of a 3.0 M solution in Et₂O, 10.2 mmol), and the mixture warmed to reflux. After 16 h, the reaction mixture was cooled to r.t., quenched with sat. NH₄Cl and extracted with CH₂Cl₂ (3×). The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo.
Ketone 3: the crude residue was purified by flash chromatography (SiO₂; hexane-EtOAc, 3:1) to afford ketone 3 (65%) as a white solid. ¹H NMR (300 MHz, CDCl₃): δ = 4.40 (1 H, d, J = 11.7 Hz), 4.03 (1 H, m), 3.67 (1 H, d, J = 11.7 Hz), 3.28 (1 H, dt, J = 12.0, 5.2 Hz), 2.95 (1 H, d, J = 11.9 Hz), 2.85 (1 H, m), 2.61 (1 H, m), 2.06 (1 H, t, J = 12.3 Hz), 1.95 (1 H, s), 1.81 (1 H, dd, J = 12.9, 5.3 Hz), 1.56 (1 H, dd, J = 14.7, 1.2 Hz), 1.34 (3 H, s), 1.22 (3 H, s), 1.17 (3 H, s), 1.15 (3 H, s), 1.12 (3 H, d, J = 7.3 Hz). ¹³C NMR (90 MHz, CDCl₃): δ = 217.5, 80.0, 79.9, 73.1, 68.6, 68.5, 64.8, 55.6, 42.2, 34.4, 32.5, 31.7, 27.0, 24.2, 22.2, 22.0. Anal. Calcd for C₁₆H₂₆O₄·0.5H₂O (%): C, 65.95; H, 9.34. Found: C, 65.59; H, 8.97.
Ketone 7: the crude residue was purified by flash chromatography (SiO₂; hexane-EtOAc, 9:1) providing ketone 7 (72%) as a white solid. ¹H NMR (300 MHz, CDCl₃): δ = 4.40 (1 H, d, J = 11.8 Hz), 3.95 (1 H, m), 3.67 (1 H, d, J = 11.8 Hz), 3.34 (1 H, dt, J = 12.0, 5.3 Hz), 2.88 (1 H, d, J = 11.9 Hz), 2.73 (1 H, dt, J = 13.8, 4.2 Hz), 2.52 (1 H, m), 2.04 (1 H, m), 1.81 (1 H, dd, J = 12.7, 5.5 Hz), 1.63 (1 H, m), 1.45 (3 H, s), 1.24 (3 H, d, J = 7.2 Hz), 1.21 (3 H, s), 1.18 (3 H, s), 1.15 (3 H, s). ¹³C NMR (90 MHz, CDCl₃): δ = 216.3, 81.1, 77.5, 73.0, 68.5, 67.9, 63.3, 55.1, 42.0, 34.9, 34.4, 31.5, 29.2, 26.0, 22.5, 20.9. IR (film): 3433, 1644 cm^-1. HRMS (FAB): m/z calcd for C₁₆H₂₇O₄ [M + H]⁺: 283.1909; found: 283.1909.
Diol 8a: The crude residue was purified by flash chromatography (SiO₂; hexane-EtOAc, 9:1) providing diol 8a as a white solid (isolated from a 1:1:1 mixture of 7:8a:9a; combined yield 82%). ¹H NMR (300 MHz, CDCl₃): δ = 4.56 (1 H, d, J = 11.6 Hz), 3.76 (1 H, m), 3.71 (2 H, m, OH), 3.66 (1 H, m), 3.24 (1 H, d, J = 11.6 Hz), 2.40 (2 H, m), 1.97 (1 H, t, J = 12.4 Hz), 1.81 (3 H, s), 1.76 (1 H, dd, J = 13.0, 6.1 Hz), 1.54 (3 H, s), 1.48 (1 H, m), 1.35 (3 H, s), 1.26 (3 H, s), 1.21 (3 H, s), 1.21 (1 H, m), 1.14 (3 H, d, J = 6.7 Hz). ¹³C NMR (90 MHz, CDCl₃): δ = 78.4, 77.5, 73.8, 73.5, 72.0, 67.4, 56.4, 43.0, 42.6, 34.4, 32.6, 31.5, 31.4, 30.6, 29.3, 23.0, 22.2. IR (film): 3336 cm^-1. HRMS (FAB): m/z calcd for C₁₇H₃₀O₄ [M + Na]⁺: 321.2042; found: 321.2042.
Ketone 9a: the crude residue was purified by flash chromatography (SiO₂; hexane-EtOAc, 9:1) providing ketone 9a as a white solid (isolated from a 1:1:1 mixture of 7:8a:9a; combined yield 82%). ¹H NMR (300 MHz, CDCl₃): δ = 4.03 (1 H, m), 4.02 (1 H, d, J = 11.0 Hz), 3.85 (1 H, dt, J = 12.1, 5.0 Hz), 3.74 (1 H, d, J = 8.6 Hz), 3.63 (1 H, d, J = 8.6 Hz), 2.33 (2 H, m), 2.07 (1 H, dd, J = 15.1, 12.6 Hz), 1.79 (4 H, m), 1.20 (9 H, s), 1.18 (6 H, s), 1.00 (3 H, d, J = 6.3 Hz). ¹³C NMR (90 MHz, CDCl₃): δ = 218.0, 73.5, 72.9, 72.8, 68.4, 61.7, 55.9, 49.3, 42.4, 35.0, 31.5, 27.3 (3C), 27.1, 22.5, 22.0. IR (film): 3413, 1692 cm^-1. HRMS (FAB): m/z calcd for C₁₇H₃₀O₄ [M + Na]⁺: 321.2042; found: 321.2012.